Prostaglandin biosynthesis inhibitory activity of some indian-1 acids in relation to their anti-inflammatory activity and ulcerogenic potency.

Continuation of our work towards development of some newer non-steroidal anti-inflammatory agents led us to some substituted indian-1-acids with low ulcerogenic liability. Prostaglandin biosynthesis inhibitory activity of these indian acids and their acid dissociation constants were evaluated in view of their activity profile.

Evaluation of some newer non-steroidal anti-inflammatory indan-1-acids in various biological systems.

In line of the effort towards development of some newer indanyl non-steroidal anti-inflammatory agents and providing comprehensive SAR among this class of compounds some significantly active derivatives with low ulcerogenic potential were identified. Dealing with various long chain and branched chain compounds among this series, 3-(5, 6-dimethoxy indan-1-yl) propionic acid, 2-(5, 6-dimethoxy indan-1-yl) propionic acid and 3-(6-methoxy indan-1-yl) propionic acid were observed to have encouraging biological activity. Screening in various animal models of inflammation suggests their longer duration of action and lower ulcerogenic liability.

Detection and distribution of scorpion (Heterometrus bengalensis) venom in rabbit tissues by enzyme-linked immunosorbent assay (ELISA).

ELISA was carried out to detect distribution of scorpion venom in experimental animal tissues. The venom content of different tissues was in the order, liver greater than kidney greater than spleen greater than lung greater than heart greater than diaphragm greater than brain. Tissue distribution of venom antigen in the envenomental subject by ELISA will provide a better approach for serotherapy.

Lethal and haemorrhagic activity of Russell's Viper venom--neutralization by polyvalent, monovalent and toxoid antiserum.

Lethal and haemorrhagic activity of Russell's Viper venom was compared against polyvalent bivalent commercial antiserum and monovalent antiserum raised in rabbit. Formaldehyde-detoxified venom offered 7-fold protection against lethal activity and 12.5-fold against haemorrhagic activity of the venom. Whole venom and formaldehyde-detoxified venom along with Freund's complete adjuvant, injected in rabbits produced high titre antiserum. Amongst all the six antiserum tested, the monovalent antiserum raised in rabbit, showed maximum precipitating bands in immunogeldiffusion and immunoelectrophoresis. The toxoid-antiserum offered maximum protection against the venom-induced lethality and the monovalent antiserum offered maximum protection against haemorrhagic activity.

Histamine, 5-HT & hyaluronidase in the venom of the scorpion Lychas laevifrons (Pock).

Factors involved in the pathophysiological changes such as severe pain, burning sensation, redness, swelling and edema in case of the scorpion L. laevifrons were investigated. The presence of pain-producing autacoids histamine 2.1 +/- 0.18 micrograms/mg and 5-HT 0.23 +/- 0.1 micrograms/ml was confirmed by thin layer chromatography and bioassay. Histamine releasing substance was detected in vitro in the chopped guineapig lung. Venom also contained hyaluronidase 5 x 10(-4) N-acetyl-D-glucosamine released/h/mg, which facilitates spread of the toxic principles in the tissues. It is concluded that histamine, 5-HT, histamine-releasing factor and hyaluronidase are partly involved in the pathophysiological changes induced by the venom. It is suggested that mepyramine and cyproheptadine may prove useful in the management of scorpion envenomation.

Isolation, partial purification and pharmacodynamics of a slow contractile substance in the venom sac extract of the wasp Vespa cincta Fabr.

The venom of V. cincta contains acetylcholine (ACh), histamine and 5-hydroxytryptamine (5-HT). Blockers of these agonists did not block completely the hypotensive and smooth muscle contractile activity of venom. On smooth muscle, there was a residual slow contraction. The active substance which produced this slow contraction was separated by solvent extraction, gel filtration and TLC. The purified material (which has been provisionally designated "Vecikinin") lowered cat, rat and guinea pig blood pressure, increased amplitude of cardiac contraction, and increased capillary permeability. Vecikinin contracted several smooth muscle preparations (rat uterus, rat ascending colon, guinea pig ileum, guinea pig colon and rat ileum), while relaxing rat duodenum. Its contractile activity was not lost on boiling, but acid or alkali-boiling reduced its contractile activity. It was inactivated on incubation with chymotrypsin and carboxypeptidase but not with trypsin, pepsin or leucine aminopeptidase. It is a peptide, appears to be of low molecular weight, and could be distinguished from substance P, angiotensin, bradykinin and hornet or wasp kinin.

Isolation and purification of a lethal scorpion toxin with neuromuscular blocking activity.

Toxin-L a lethal neuromuscular blocking agent was isolated from the venom of the scorpion, Lychas laevifrons (Pocock), by the CM-cellulose ion-exchange chromatography. It was a homogenous, thermolabile and low molecular weight protein. The toxin produced irreversible blockade of indirect stimulation induced twitch responses on innervated rat phrenic nerve-diaphragm and chick biventer cervicis preparation. The toxin did not produce any contractile response on toad rectus abdominis muscle preparation. On chronically denervated rat diaphragm, the toxin failed to alter the responses induced by direct stimulation, exogenous acetylcholine, potassium chloride and caffeine. Acetylcholine and carbachol induced contractions on isolated chick biventer cervicis remained unaltered by the toxin. Neostigmine failed to alter toxin induced neuromuscular blockade on innervated rat diaphragm. The toxin released a significant amount of acetylcholine from innervated rat diaphragm. It may be concluded that the toxin acts presynaptically through the release of acetylcholine, thereby producing neuromuscular blockade.

Studies on non-steroidal anti-inflammatory and related biological activities of 5-(indan-1'-yl)tetrazoles and their intermediates.

Anti-inflammatory, analgesic and anti-pyretic activities of three new 5-(Indan-1'-yl)tetrazoles and anti-inflammatory activity of corresponding carboxamides were compared to those of standard drugs, phenylbutazone and aspirin. The results indicated 5-(Indan-1'-yl)tetrazole as the most promising compound in chronic anti-inflammatory and anti-pyretic tests.

Isolation, purification and immunological evaluation of toxin Hb from scorpion Heterometrus bengalensis (C.L. Koch) venom.

Toxin-Hb, a lethal toxic antigenic protein, isolated from the venom of H. bengalensis by CM-cellulose ion-exchange chromatography was a heat labile basic protein with a molecular weight of 10 kDa. It produced irreversible blockade on the isolated rat phrenic nerve diaphragm and chick biventer cervicis. LD50 of toxin Hb was 0.48 mg/kg (iv) in mice. Antiserum was raised in mice by hyperimmunization against toxin Hb. Antitoxin Hb antiserum was immunologically potent as revealed by immunogel-diffusion and immunoelectrophoresis. Five fold protection against the lethal action of toxin Hb was achieved by the antiserum. It also effectively antagonised toxin Hb induced neuromuscular blockade on isolated rat phrenic nerve diaphragm and chick biventer cervicis preparations.

Pharmacology of scorpion (Lychas laevifrons Pock) venom with special reference to its neuromuscular activity.

L. laevifrons venom caused irreversible blockade of electrically induced twitch responses on phrenic nerve diaphragm and chick biventer cervicis preparation. The venom lowered cat blood pressure, caused a brief cardiac arrest and increased cutaneous capillary permeability. It contracted several smooth muscle preparations. The quick contraction produced on guinea pig ileum was partly antagonized by mepyramine and completely by methysergide. The residual slow contraction was antagonized by SC 19220, a prostaglandin blocker. Haemolysis was not produced by the venom on human RBC. LD50 of crude venom in mice was 13.8 mg/kg (iv).

Comparative detoxification and protection of scorpion (Heterometrus bengalensis) venom by toxoid antiserum.

Comparative detoxification of scorpion venom by using different chemical agents was investigated. Detoxification by formalin showed the best optimum detoxifying agent. The formalin treatment resulted in 2.3% protein loss with 6-fold detoxification. This formal toxoid was immunogenic in rabbit giving high neutralizing antibodies as revealed from indirect haemagglutination test. Toxoid antiserum protected mice against the lethal action of venom. It also effectively antagonized the smooth muscle contractile response of venom, and venom-induced neuromuscular paralysis. This toxoid antiserum also protected the venom-induced cardiac arrest. The possibility of using this formal toxoid for antisera production and immunization for therapeutic use needs to be explored.

Immunological cross reactivity & paraspecificity of the scorpion Heterometrus bengalensis antivenom.

Immunological cross-reactivity and paraspecificity of scorpion H. bengalensis antivenom were studied to find out the intergeneric therapeutic relationship between the venom of other scorpions in West Bengal Buthus tamulus, Lychas laevifrons and Heterometrus swammerdami. Of these scorpions, Buthus tamulus and Lychas laevifrons failed to show any cross reactivity. However, H. swammerdami venom showed cross-reactivity with H. bengalensis antiserum as revealed from immunogeldiffusion and immunoelectrophoresis. This antiserum protected H. swammerdami venom-induced lethality in mice, blocked the contractile response in smooth muscles and antagonised the venom-induced neuromuscular blockade in rat phrenic nerve diaphragm and chick biventer cervicis.

Pharmacological and immunological evaluation of scorpion (Heterometrus bengalensis) venom antiserum.

An antiserum was prepared for the first time against the venom of a common scorpion, H. bengalensis, by hyperimmunization of rabbit. This antiserum showed positive precipitin bands in immunogeldiffusion and immunoelectrophoresis. The serum showed a high titre value tested by indirect haemagglutination test. The antiserum developed in rabbit protected mice against the lethal action of the venom. Smooth muscle contractile response of venom on guinea pig ileum, and rat uterus was antagonized by the antiserum. This antiserum effectively antagonized the venom induced neuromuscular paralysis tested on rat phrenic nerve diaphragm and chick biventer cervices. Antiserum also protected the venom-induced cardiac arrest tested on isolated guineapig heart and auricle preparations.

Anti-inflammatory derivatives of indan-1-acetic acids with low gastric irritancy.

In an attempt to minimize the gastric ulcerogenicity of 6-methoxyindan-1-acetic acid and 5,6-dimethoxyindan-1-acetic acid exhibiting high anti-inflammatory activity, we synthesized their esters, amides and nitrile derivatives. It was found that the anti-inflammatory activity of ethyl esters were almost equal to those of parent acids and phenylbutazone while other derivatives were less potent. Those ethyl esters were also found to be much less ulcerogenic than phenylbutazone.